Project Summary According to WHO estimates, neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. It is manifested by deficits in adaptive behaviors in everyday social and practical skills, which can have a devastating effect on the lives of affected individuals and their families. Due to its high prevalence of 2-3%,2; 3 and the lifetime cost of care per individual in the range of $1-2 million in United Sates,4 ID presents a significant health burden and is a major challenge at the clinical level. Genetic factors are involved in the etiology of 25-50% of ID cases. 2 Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However the identity of a large number of essential molecular and cellular components remain unknown. The Objective of the proposed research is to identify and characterize genes/proteins essential for autosomal recessive ID (ARID). The rationale is that identification of causative gene variants that lead to ARID and elucidation of the functions of normal genes will be essential for understanding brain function and developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders in general and ID in particular. The project addresses NIH?s mission to generate basic knowledge that may be translatable to reduce the burden of human diseases. There are 3 aims: 1) Ascertain and clinically phenotype members of extended families segregating ARID; 2) identify new ARID genes and gene products; and 3) determine synaptic functions of prioritized novel ARID genes, by analyzing spatiotemporal expression patterns in mouse brain, synaptic targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology, live-cell imaging, and in utero electroporation assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutics targets to slow progression, delay onset, and possibly treat some forms of ID.